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ABSTRACT: We have identified a distinctive lymphoid-restricted progenitor population in adult mouse bone marrow based on a unique c-Kit(-)Sca-1(high)Flt3(+) AA4(+) surface phenotype. These cells are highly lymphoid biased and rapidly generate B and T cells after adoptive transfer. However, whereas previously described lymphoid progenitors such as common lymphoid progenitors express TdT and relatively high levels of RAG2, and are enriched for cells with an active V(D)J recombinase, Flt3(+) AA4(+) cells within the c-Kit(-)Sca-1(high) bone marrow fraction are TdT(-), are RAG2(low), and do not display evidence for ongoing or past recombinase activity. Furthermore, unlike common lymphoid progenitors that readily generate B cells upon stimulation with IL-7, c-Kit(-)Sca-1(high)Flt3(+) precursors do not express abundant levels of the IL-7R, and require costimulation with Flt3 ligand and IL-7 to generate B cells in vitro. Moreover, these findings suggest that hematopoietic stem cells in adults generate an array of lymphoid-biased progenitor populations characterized by distinct gene expression and cytokine response profiles.
The Journal of Immunology 01/2009; 181(11):7514-24. · 5.79 Impact Factor
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ABSTRACT: To generate T cells throughout adult life, the thymus must import hemopoietic progenitors from the bone marrow via the blood. In this study, we establish that thymus settling is selective. Using nonirradiated recipient mice, we found that hemopoietic stem cells were excluded from the thymus, whereas downstream multipotent progenitors (MPP) and common lymphoid progenitors rapidly generated T cells following i.v. transfer. This cellular specificity correlated with the expression of the chemokine receptor CCR9 by a subset of MPP and common lymphoid progenitors but not hemopoietic stem cells. Furthermore, CCR9 expression was required for efficient thymus settling. Finally, we demonstrate that a prethymic signal through the cytokine receptor fms-like tyrosine kinase receptor-3 was required for the generation of CCR9-expressing early lymphoid progenitors, which were the most efficient progenitors of T cells within the MPP population. We conclude that fms-like tyrosine kinase receptor-3 signaling is required for the generation of T lineage-competent progenitors, which selectively express molecules, including CCR9, that allow them to settle within the thymus.
The Journal of Immunology 03/2007; 178(4):2008-17. · 5.79 Impact Factor
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ABSTRACT: Current models predict that mouse plasmacytoid dendritic cells (PDCs) derive from lymphoid progenitors. However, we show PDCs arise exclusively from common myeloid progenitors (CMPs) characterized by low-level expression of several lymphoid-associated genes, including a RAG2/GFP reporter transgene. This conclusion is supported by both adoptive transfer experiments and an estrogen treatment strategy that led to marked depletion of very early lymphoid progenitors without affecting RAG2/GFP(+) CMPs or the developmental kinetics, RAG-mediated recombinase activity, and cytokine production of PDCs. These data suggest that PDCs arise exclusively from early myeloid progenitors and that promiscuous low-level expression of lymphoid-associated genes is a general feature of PDC progenitors among CMPs.
Blood 09/2006; 108(3):878-85. · 9.90 Impact Factor
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ABSTRACT: Commitment of hemopoietic progenitors to the T-cell lineage is a crucial requirement for T-cell development, yet the timing and developmental cues regulating this process remain controversial. Here we have devised a technique to analyze the T-cell/B-cell lineage potential of precursors that have been recruited to the fetal mouse thymus but which have yet to contact the thymic epithelial microenvironment. We show that lymphoid progenitors arriving at the thymus are not bipotent T/B precursors, and provide evidence that intrathymic Notch signaling is not the mechanism determining T/B lineage choice in migrant precursors. Rather, we provide evidence that Notch signaling influences T/B lineage choice in lymphoid precursors through interactions with defined stromal components within the fetal liver. Collectively, our data redefine our understanding of the role and timing of Notch signaling in relation to lineage choices in lymphoid precursors.
Blood 09/2005; 106(3):886-92. · 9.90 Impact Factor
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ABSTRACT: T cells develop in the thymus from blood-borne progenitors derived from haematopoietic tissues. Amongst the mechanisms by which stromal cells in thymic and prethymic tissues influence lymphoid progenitors, recent attention has focussed on the importance of Notch signalling in early T cell development. Here, we review evidence that developing T cells and their progenitors receive signals through Notch receptors as a result of interactions with Notch ligands expressed by stromal cells. In particular, we focus on the role of Notch ligand-expressing stromal cells in regulating key control points during pre- and intrathymic phases of T cell development.
Seminars in Immunology 05/2003; 15(2):91-7. · 6.39 Impact Factor
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ABSTRACT: Interactions between T cell precursors and thymic stromal cells are essential during thymocyte development. However, the role of the thymus in initial commitment of lymphoid progenitors to the T lineage remains controversial, with data providing evidence for both extra- and intrathymic commitment mechanisms. In this context, it is clear that Notch1 is an important mediator during initiation of T cell development. Here we have analyzed the mechanisms regulating Notch activation in lymphoid precursors at extrathymic sites and in the thymus, including stages representing the first wave of embryonic thymus colonization on embryonic day 12 of gestation. We show that Notch activation in migrant lymphoid precursors requires entry into the thymic microenvironment where they are exposed to Notch ligands expressed by immature thymic epithelial cells. Moreover, continued Notch signaling in such precursors requires sustained interactions with Notch ligands. Collectively, these findings suggest a role for Notch in an intrathymic mechanism of T cell lineage commitment involving sustained interactions with Notch ligand bearing thymic epithelium.
The Journal of Immunology 03/2003; 170(3):1299-303. · 5.79 Impact Factor
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ABSTRACT: T cell development in the thymus occurs through a series of events beginning with thymic colonization by migrant precursors and ending with the emigration of functionally competent CD4+and CD8+T cells to the periphery. It is well accepted that signals through the pre-T cell receptor (pre-TCR) and alpha-beta TCR (αβ TCR) complex play pivotal roles in the maturation of CD4−8−and CD4+8+thymocytes, respectively. It is clear that stromal cells constituting the thymic microenvironment provide non-TCR-mediated interactions which are essential for several developmental events. Examples of such will be discussed here in relation to early and late events in T cell development.
Seminars in Immunology 11/2000; · 6.39 Impact Factor
